[CANCER RESEARCH 48. 493-496. February I. 1988] Perspectives in Cancer Research Oncogenes of DNA Tumor Viruses1 Arnold J. Levine Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544 Experiments carried out over the past 10-12 years have the cellular oncogenes. It will attempt to identify where more created a field or approach which may properly be termed the information is required or contradictions appear in the devel molecular basis of cancer. One of its major accomplishments oping concepts. Finally, this communication will examine ex has been the identification and understanding of some of the amples of cooperation between oncogenes and other gene prod functions of a group of cancer-causing genes, the oncogenes. ucts which modify the mode of action of the former. If we are The major path to the oncogenes came from the study of cancer- on the right track, then general principles may well emerge. causing viruses. The oncogenes have been recognized and stud Tumor formation in animals or transformation in cell culture ied by two separate but related groups of virologists focusing has been demonstrated with many different DNA-containing upon either the DNA (1) or RNA (2) tumor viruses (they even viruses (1). In most cases it has been possible to identify one or have separate meetings now that these fields have grown so a few viral genes and their products that are responsible for large). From their studies it has become clear that the oncogenes transformation or, in some cases, tumorigenesis. A list of these of each virus type have very different origins. Indeed it is a viral gene products is presented in Table 1. With two notable curious fact that virtually every group of the DNA viruses exceptions, infection of cells and selection for the transformed studied (papova-papilloma, adenoviruses, herpesviruses, hepad- phenotype always result in a clone of cells containing and naviruses, poxviruses) has a representative virus which has been expressing viral gene products (1) and in some cases, these viral shown to produce, or be closely associated with, tumors in proteins have been shown to be required for the maintenance animals. Many DNA viruses have been shown to be tumor of the transformed state (14). The first exception is HSV2-1 or viruses under the appropriate and often specialized circum -2 and CMV, where it has been difficult to find reproducible stances of an experiment (1). In contrast, among the thousands viral genetic information or gene products in transformed cells of RNA viruses, only the retroviruses contain examples of viral (15, 16). Several explanations have been put forth to account agents that cause tumors. While the viral oncogenes that reside for these observations: (a) a "hit-and-run" hypothesis where the in the genome of the DNA tumor viruses bear little or no viral gene products act (via inducing mutation, for example) homology to cellular genes, the oncogenes of retroviruses are and are then no longer required (17); (b) insertion of a small clearly derived from and are closely related to their cellular viral DNA element (a promoter, for example) in the chromo counterparts, the protooncogenes (3). The evidence demonstra some activating a cellular oncogene (16). The insertion-pro ting that viral (DNA tumor viruses) and cellular (RNA tumor moter model, demonstrated with other viruses (18), has yet to viruses) derived oncogenes participate in the development of a be proven with HSV or CMV; (c) the frequency of HSV or cancer cell is quite convincing and accepted by most critical CMV transformation in cell culture is so low (at background scientists in the field, but not without some reservations (4, 5). level) (15, 16) that no real proof exists for the transforming Research, pursuing the isolation and functions of the cellular abilities of these viruses. In this case no explanation or mech oncogenes, has proceeded rapidly and been very productive with anism of transformation would be required. Epidemiological frequent reviews of this field (6-8). Less visible but equally evidence for the role of HSV-1 or -2 or CMV in human cancer valuable is the information accumulating about the viral onco is not convincing and what was accepted previously (HSV-2 genes of DNA tumor viruses. The justifications for focusing on and cervical carcinoma) is, in light of new data, no longer held this topic are, in the end, the same reasons why the cellular to be correct (19). The other example of a DNA virus with no oncogenes are important in the understanding of cancer: (a) known oncogene or protooncogene is hepatitis B virus. The some of the DNA tumor viruses (human papilloma viruses 16, epidemiological association between chronic hepatitis B virus 18, 33; hepatitis B virus; Epstein-Barr virus) are closely and infection and hepatocellular carcinoma is quite excellent (10); continuously associated with specific human cancers and prob however, the mechanism of carcinogenic action is unclear. ably contribute to one of several events that cause these cancers Some ideas such as (a) an increased risk of mutagenic or (9-11); (b) a study of the mechanisms of action of these viral carcinogenic events following destruction caused by chronic oncogenes will provide fundamental information about the infection, (b) the polymerase of the virus (reverse transcriptase) control of cell growth. There is already good evidence that some has a high error frequency and acts as a "mutator gene", and viral transforming gene products act upon normal cellular pro (c) a yet-to-be-found HBV protein that can act as an oncogene tooncogene products and alter their activities or levels (12,13). or cooperate with an oncogene (i.e., we still need an assay to Other viral oncogenes act to bypass the normal cellular control detect it), have all been put forth to explain these data. The mechanisms regulated by the protooncogenes and their prod development of model systems such as transgenic animals car ucts. A little consideration and several key experiments lead to rying this virus or some isolated viral genes could go a long the conclusion that a study of the DNA viral oncogenes will way to testing some of these ideas (20). inevitably bring us back to the cellular protooncogenes. The majority of the DNA tumor viruses (Table 1) have genes The goal of this "Perspective" will be to focus upon the DNA that encode protein products that actively participate in the virus oncogenes and their interactions and relationships with creation of a cancer cell and the transformed phenotype (1). Received 10/1/87; accepted 10/28/87. 2The abbreviations used are: HSV, herpes simplex virus; CMV, cytomegalovi- 1This work was supported by Grants CA09528 and CA38757 from N1H and rus; BPV, bovine papilloma virus; EBV, Epstein-Barr virus; EGF, epidermal MV-47 from the American Cancer Society. growth factor; p53, a protein with a molecular weight of 53,000. 493 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 1988 American Association for Cancer Research. DNA TUMOR VIRUS ONCOGENES Table l DNA tumor virus oncogena Functions, location, mode Viruses Oncogenes of action Papovaviruses SV40 Large T-antigen Nucleus-membrane, +/—*transcription, mitogenic, tumor- specific transplantation antigen, complex-p53 Small t-antigen Cytoplasm Polyoma Large T-antigen Nucleus, +/—transcription, DNA synthesis Middle t-antigen Inner plasma membrane, perinuclear membranes, complex-sir Small t-antigen Cytoplasmic Papillomaviruses (BPV, human) ES protein Plasma membrane E6 protein Nucleus, membrane Adenoviruses E\\-M, 26,000 —transcription E \\-M, 36,000 + transcription E1B-AÕ,21,000 Nuclear membrane E\B-M, 55,000 mRNA transport, complex-p53 Herpesviruses Epstein-Barr virus Lymphoproliferative Latent membrane protein malignancy Epstein-Barr nuclear Nuclear antigen antigen-II Herpes simplex types 1 and 2 Cytomegalovirus Hepadnaviruses Hepatitis B virus Poxviruses (vaccinia) Vaccinia growth factor Related to EGF and transforming growth factor-a; binds to Rabbit fibroma EGF receptor-mitogen Yaba tumor virus Fowlpox These may be proteins localized in the nucleus (SV40-polyoma residues deleted, and so increased enzyme activity is achieved large T-antigen, BPV-E6, adenovirus EIA, El B proteins, EBV- via a similar loss of regulation (2). The second interaction of a Epstein-Barr nuclear antigen-2), in the cytoplasm (small t- viral transforming gene product with a cellular protooncogene antigens SV40, polyoma), or in or on the plasma membrane is observed with the SV40 large T-antigen-p53 association (12, (BPV-E5, Py middle t, EBV-LMP) (1). Some of these viral 31). In normal cells, p53 protein levels are kept low due to the oncogenes are tumor-specific transplantation antigens (SV40 short half-life (6-20 min) of this protein. In many transformed large T-antigen, probably adenovirus EIA) (21, 22) or are cells, p53 levels are 10 to 100-fold higher and the half-life of recognized by T-lymphocytes (the EBV-latent membrane pro p53 is much increased (32). In SV40 transformed cells, p53 is tein is likely to be the lymphocyte determined membrane anti found in an oligomeric protein complex with SV40 T-antigen, gen or LYDMA) (23). There has been a wide variety of func and temperature-sensitive mutants of T-antigen regulate p53 tions associated with these proteins. The SV40 large T-antigen levels in a temperature-sensitive fashion (33). p53 has been and adenovirus EIA gene products can negatively or positively shown to be an oncogene because complementary DNA clones regulate transcription of viral and probably cellular genes (24, of p53 can immortalize cells in culture (34) and cooperate with 25). The adenovirus ElB-A/r 55,000 protein appears to be the ras oncogene to transform primary rat cells (35). Indeed, involved in mRNA transport from the nuclear to the cyto p53 is the only oncogene to date which was first described by plasm ic compartments (26).